Publications by authors named "Gerda M Steup-Beekman"

37 Publications

White matter hyperintensities associate with cognitive slowing in patients with systemic lupus erythematosus and neuropsychiatric symptoms.

RMD Open 2021 Jul;7(2)

Department of Radiology, Leiden University Medical Centre, Leiden, the Netherlands.

Objective: To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter hyperintensity (WMH) volumes.

Methods: Patients attending the Leiden University Medical Centre NPSLE clinic between 2007 and 2015 without large brain infarcts were included (n=151; 42±13 years, 91% women). In a multidisciplinary consensus meeting, neuropsychiatric symptoms were attributed to systemic lupus erythematosus (SLE) (NPSLE, inflammatory (n=24) or ischaemic (n=12)) or to minor/non-NPSLE (n=115). Multiple regression analyses were performed to compare cognitive function between NPSLE phenotypes and to assess associations between brain and WMH volumes and cognitive function cross-sectionally.

Results: Global cognitive function was impaired in 5%, learning and memory (LM) in 46%, executive function and complex attention (EFCA) in 39% and psychomotor speed (PS) in 46% of all patients. Patients with inflammatory NPSLE showed the most cognitive impairment in all domains (p≤0.05).Higher WMH volume associated with lower PS in the total group (B: -0.14 (95% CI -0.32 to -0.02)); especially in inflammatory NPSLE (B: -0.36 (95% CI -0.60 to -0.12). In the total group, lower total brain volume and grey matter volume associated with lower cognitive functioning in all domains (all: 0.00/0.01 (0.00;0.01)) and lower white matter volume associated with lower LM, EFCA and PS (all: 0.00/0.01 (0.00;0.01)).

Conclusion: We demonstrated that an association between brain and WMH volumes and cognitive function is present in patients with SLE, but differs between (NP)SLE phenotypes. WMHs associated with PS especially in inflammatory NPSLE, which suggests a different, potentially more severe underlying pathophysiological mechanism of cognitive impairment in this phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/rmdopen-2021-001650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320250PMC
July 2021

Different phenotypes of neuropsychiatric systemic lupus erythematosus are related to a distinct pattern of structural changes on brain MRI.

Eur Radiol 2021 Apr 30. Epub 2021 Apr 30.

Department of Radiology, Leiden University Medical Center (LUMC), Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.

Objectives: The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain tissue volumes between a clinically well-defined cohort of patients with NPSLE and SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). Within the NPSLE patients, we also examined differences between patients with two distinct disease phenotypes: ischemic and inflammatory.

Methods: In this prospective (May 2007 to April 2015) cohort study, we included 38 NPSLE patients (26 inflammatory and 12 ischemic) and 117 non-NPSLE patients. All patients underwent a 3-T brain MRI scan that was used to automatically determine white matter, grey matter, white matter hyperintensities (WMH) and total brain volumes. Group differences in brain tissue volumes were studied with linear regression analyses corrected for age, gender, and total intracranial volume and expressed as B values and 95% confidence intervals.

Results: NPSLE patients showed higher WMH volume compared to non-NPSLE patients (p = 0.004). NPSLE inflammatory patients showed lower total brain (p = 0.014) and white matter volumes (p = 0.020), and higher WMH volume (p = 0.002) compared to non-NPSLE patients. Additionally, NPSLE inflammatory patients showed lower white matter (p = 0.020) and total brain volumes (p = 0.038) compared to NPSLE ischemic patients.

Conclusion: We showed that different phenotypes of NPSLE were related to distinct patterns of underlying structural brain MRI changes. Especially the inflammatory phenotype of NPSLE was associated with the most pronounced brain volume changes, which might facilitate the diagnostic process in SLE patients with neuropsychiatric symptoms.

Key Points: • Neuropsychiatric systemic lupus erythematosus (NPSLE) patients showed a higher WMH volume compared to SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). • NPSLE patients with inflammatory phenotype showed a lower total brain and white matter volume, and a higher volume of white matter hyperintensities, compared to non-NPSLE patients. • NPSLE patients with inflammatory phenotype showed lower white matter and total brain volumes compared to NPSLE patients with ischemic phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-021-07970-2DOI Listing
April 2021

Fatigue in patients with systemic lupus erythematosus and neuropsychiatric symptoms is associated with anxiety and depression rather than inflammatory disease activity.

Lupus 2021 Jun 28;30(7):1124-1132. Epub 2021 Mar 28.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Introduction: We aimed to investigate risk factors for fatigue in patients with systemic lupus erythematosus (SLE) and neuropsychiatric symptoms in order to identify potential interventional strategies.

Methods: Patients visiting the neuropsychiatric SLE (NPSLE) clinic of the Leiden University Medical Center between 2007-2019 were included. In a multidisciplinary consensus meeting, SLE patients were classified as having neuropsychiatric symptoms of inflammatory origin (inflammatory phenotype) or other origin (non-inflammatory phenotype). Fatigue was assessed with the SF-36 vitality domain (VT) since 2007 and the multidimensional fatigue inventory (MFI) and visual analogue scale (VAS) since 2011. Patients with a score on the SF-36 VT ≥1 standard deviation (SD) away from the mean of age-related controls of the general population were classified as fatigued; patients ≥2 SD away were classified as extremely fatigued. Disease activity was measured using the SLE disease activity index-2000. The influence of the presence of an inflammatory phenotype, disease activity and symptoms of depression and anxiety as measured by the hospital anxiety and depression scale (HADS) was analyzed using multiple regression analyses corrected for age, sex and education.

Results: 348 out of 371 eligible patients filled in questionnaires and were included in this study . The majority was female (87%) and the mean age was 43 ± 14 years. 72 patients (21%) had neuropsychiatric symptoms of an inflammatory origin. Fatigue was present in 78% of all patients and extreme fatigue was present in 50% of patients with an inflammatory phenotype vs 46% in the non-inflammatory phenotype. Fatigue was similar in patients with an inflammatory phenotype compared to patients with a non-inflammatory phenotype on the SF-36 VT (β: 0.8 (95% CI -4.8; 6.1) and there was less fatigue in patients with an inflammatory phenotype on the MFI and VAS (β: -3.7 (95% CI: -6.9; -0.5) and β: -1.0 (95% CI -1.6; -0.3)). There was no association between disease activity and fatigue, but symptoms of anxiety and depression (HADS) associated strongly with all fatigue measurements.

Conclusion: This study suggests that intervention strategies to target fatigue in (NP)SLE patients may need to focus on symptoms of anxiety and depression rather than immunosuppressive treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/09612033211005014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120630PMC
June 2021

Longitudinal changes in cerebral white matter microstructure in newly diagnosed systemic lupus erythematosus patients.

Rheumatology (Oxford) 2021 06;60(6):2678-2687

Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.

Objectives: To evaluate longitudinal variations in diffusion tensor imaging (DTI) metrics of different white matter (WM) tracts of newly diagnosed SLE patients, and to assess whether DTI changes relate to changes in clinical characteristics over time.

Methods: A total of 17 newly diagnosed SLE patients (19-55 years) were assessed within 24 months from diagnosis with brain MRI (1.5 T Philips Achieva) at baseline, and after at least 12 months. Fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity values were calculated in several normal-appearing WM tracts. Longitudinal variations in DTI metrics were analysed by repeated measures analysis of variance. DTI changes were separately assessed for 21 WM tracts. Associations between longitudinal alterations of DTI metrics and clinical variables (SLEDAI-2K, complement levels, glucocorticoid dosage) were evaluated using adjusted Spearman correlation analysis.

Results: Mean MD and RD values from the normal-appearing WM significantly increased over time (P = 0.019 and P = 0.021, respectively). A significant increase in RD (P = 0.005) and MD (P = 0.012) was found in the left posterior limb of the internal capsule; RD significantly increased in the left retro-lenticular part of the internal capsule (P = 0.013), and fractional anisotropy significantly decreased in the left corticospinal tract (P = 0.029). No significant correlation was found between the longitudinal change in DTI metrics and the change in clinical measures.

Conclusion: Increase in diffusivity, reflecting a compromised WM tissue microstructure, starts in initial phases of the SLE disease course, even in the absence of overt neuropsychiatric (NP) symptoms. These results indicate the importance of monitoring NP involvement in SLE, even shortly after diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keaa677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213425PMC
June 2021

Suspected Transverse Myelitis with Normal MRI and CSF Findings in a Patient with Lupus: What to Do? A Case Series and Systematic Review.

Neuropsychiatr Dis Treat 2020 22;16:3173-3186. Epub 2020 Dec 22.

Department of Rheumatology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.

Purpose: To evaluate the use of immunosuppressive treatment, clinical outcome and diagnostic strategy in patients with systemic lupus erythematosus (SLE) presenting with clinical features of transverse myelitis (TM), but normal MRI of the spinal cord (sMRI) and normal cerebrospinal fluid (CSF) assessment, and to suggest a clinical guideline.

Patients And Methods: All patients with SLE and clinical features compatible with (sub)acute TM visiting the NPSLE clinic of the LUMC between 2007 and 2020 were included. Information on baseline characteristics, investigations, treatment and outcomes was collected from electronic medical records. In addition, a systematic review of individual participant data was performed up to April 2020 in PubMed, Embase and Web of Science, identifying all patients with TM, SLE and sMRI assessment. Data regarding sMRI, CSF analysis, treatment and outcome were extracted, and outcome was compared between patients with normal sMRI and CSF (sMRI-/CSF-) and patients with abnormalities.

Results: Twelve SLE patients with a clinical diagnosis of TM were identified: four sMRI-/CSF- and one sMRI- with CSF not available. All patients received immunosuppressive treatment, but outcome in sMRI-/CSF- patients was worse: no recovery (n=1) or partial recovery (n=3) compared to partial recovery (n=4) and (nearly) complete recovery (n=3) in MRI+ patients. The systematic literature review yielded 146 articles eligible for inclusion, 90% case reports. A total of 427 SLE patients with TM were identified, of which only four cases were sMRI-/CSF- (1%), showing no improvement (n=1), partial improvement (n=2) and complete recovery (n=1) after immunosuppressive treatment.

Conclusion: Outcome in SLE patients presenting with clinically suspected TM with normal sMRI and CSF is less favorable, despite treatment with immunosuppressive therapy. Taking a functional neurological disorder into consideration may be helpful in order to start other therapeutic strategies. We suggest prescribing immunosuppressive treatment for a restricted period of time to evaluate its effect in cases where a functional disorder initially is considered unlikely.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/NDT.S267000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764958PMC
December 2020

Mortality in patients with systemic lupus erythematosus and neuropsychiatric involvement: A retrospective analysis from a tertiary referral center in the Netherlands.

Lupus 2020 Dec 20;29(14):1892-1901. Epub 2020 Oct 20.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Objective: We aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018.

Methods: Patients visiting the tertiary referral NPSLE clinic of the Leiden University Medical Center were included. NP symptoms were attributed to SLE requiring treatment (major NPSLE) or to other and mild causes (minor/non-NPSLE). Municipal registries were checked for current status (alive/deceased). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using data from the Dutch population. Rate ratio (RR) and 95% CI were calculated using direct standardization to compare mortality between major NPSLE and minor/non-NPSLE.

Results: 351 patients were included and 149 patients were classified as major NPSLE (42.5%). Compared with the general population, mortality was increased in major NPSLE (SMR 5.0 (95% CI: 2.6-8.5)) and minor/non-NPSLE patients (SMR 3.7 (95% CI: 2.2-6.0)). Compared with minor/non-NPSLE, mortality was similar in major NPSLE patients (RR: 1.0 (95% CI: 0.5-2.0)). Cause-specific mortality rates demonstrated an increased risk of death due to infections in both groups, whereas death due to cardiovascular disease was only increased in minor/non-NPSLE patients.

Conclusion: Mortality was increased in both major NPSLE and minor/non-NPSLE patients in comparison with the general population. There was no difference in mortality between major NPSLE and minor/non-NPSLE patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0961203320963815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684795PMC
December 2020

TREAT Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid arthritis (TREAT EARLIER): a randomized, double-blind, placebo-controlled clinical trial protocol.

Trials 2020 Oct 16;21(1):862. Epub 2020 Oct 16.

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Background: We present a study protocol for a randomized, double-blind, placebo-controlled trial that investigates the hypothesis if intervention in the symptomatic phase preceding clinical arthritis (clinically suspect arthralgia (CSA)) is effective in preventing progression from subclinical inflammation to clinically apparent persistent arthritis. Currently, rheumatoid arthritis (RA) can be recognized and diagnosed when arthritis (joint swelling) has become detectable at physical examination. Importantly, at this time, the immune processes have already matured, chronicity is established, and patients require long-standing treatment with disease-modifying anti-rheumatic drugs. The TREAT EARLIER trial studies the hypothesis that intervention in the symptomatic phase preceding clinical arthritis is more often successful in permanent disease modification because of less matured underlying disease processes.

Methods: A two-level definition to identify patients that are prone to develop RA is used. First, patients should have CSA and recent-onset arthralgia (< 1 year) that is suspect to progress to RA according to the expertise of the treating rheumatologist. Second, patients need to have subclinical inflammation of the hand or foot joints at 1.5 T MRI. The trial aims to recruit 230 participants from secondary care hospital settings across the south-west region of The Netherlands. Intervention will be randomly assigned and includes a single-dose of intramuscular 120 mg methylprednisolon followed by methotrexate (increasing dose to 25 mg/week orally) or placebo (both; injection and tablets) over the course of 1 year. Thereafter, participants are followed for another year. The primary endpoint is the development of clinically detectable arthritis, either fulfilling the 2010 criteria for RA or unclassified clinical arthritis of ≥ 2 joints, which persists for at least 2 weeks. DMARD-free status is a co-primary endpoint. The patient-reported outcomes functioning, along with workability and symptoms, are key secondary endpoints. Participants, caregivers (including those assessing the endpoints), and scientific staff are all blinded to the group assignment.

Discussion: This proof-of-concept study is the logical consequence of pre-work on the identification of patients with CSA with MRI-detected subclinical joint inflammation. It will test the hypothesis whether intervention in patients in this early phase with the cornerstone treatment of classified RA (methotrexate) hampers the development of persistent RA and reduce the disease burden of RA.

Trial Registration: Dutch Trial Register NL4599 (NTR4853). Registered on 20 October 2014.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-020-04731-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574479PMC
October 2020

Left Ventricular Systolic Function in Patients with Systemic Lupus Erythematosus and Its Association with Cardiovascular Events.

J Am Soc Echocardiogr 2020 09 1;33(9):1116-1122. Epub 2020 Jul 1.

Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with potential cardiovascular involvement. The aim of this study was to assess left ventricular (LV) systolic function in a large cohort of patients with SLE using standard echocardiographic measurements and global longitudinal strain (GLS) by two-dimensional speckle-tracking analysis. Furthermore, the association between echocardiographic parameters and the occurrence of cardiovascular events was assessed.

Methods: A total of 102 patients with SLE (88% women; mean age, 43 ± 14 years) undergoing a dedicated multidisciplinary assessment were analyzed, including echocardiography, at the time of their first visit. A control group consisted of 50 age- and sex-matched healthy subjects.

Results: Compared with control subjects, patients with SLE showed impaired LV systolic function on the basis of LV ejection fraction (51 ± 6% vs 62 ± 6%, P < .001) and by LV GLS (-15 ± 3% vs -19 ± 2%, P < .001). During a median follow-up period of 2 years (interquartile range, 1-6 years), 38 patients (37%) developed cardiovascular events. Kaplan-Meier survival curves showed that patients with SLE with more impaired LV GLS (on the basis of the median value of -15%) experienced higher cumulative rates of cardiovascular events compared with those with less impaired LV GLS (χ = 8.292, log-rank P = .004). On multivariate Cox regression analysis, LV GLS demonstrated an independent association with cardiovascular events (hazard ratio, 2.171; 95% CI, 1.015-4.642; P = .046), whereas LV ejection fraction was not significantly associated with the outcome.

Conclusions: In patients with SLE, LV systolic function as measured by LV GLS is significantly impaired and associated with cardiovascular events, potentially representing a new tool to improve risk stratification in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.echo.2020.04.018DOI Listing
September 2020

Laboratory and Neuroimaging Biomarkers in Neuropsychiatric Systemic Lupus Erythematosus: Where Do We Stand, Where To Go?

Front Med (Lausanne) 2018 4;5:340. Epub 2018 Dec 4.

Department of Radiology, C.J. Gorter Center for High Field MRI, Leiden University Medical Center, Leiden, Netherlands.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multi-systemic involvement. Nervous system involvement in SLE leads to a series of uncommon and heterogeneous neuropsychiatric (NP) manifestations. Current knowledge on the underlying pathogenic processes and their subsequent pathophysiological changes leading to NP-SLE manifestations is incomplete. Several putative laboratory biomarkers have been proposed as contributors to the genesis of SLE-related nervous system damage. Alongside the laboratory biomarkers, several neuroimaging tools have shown to reflect the nature of tissue microstructural damage associated with SLE, and thus were suggested to contribute to the understanding of the pathophysiological changes and subsequently help in clinical decision making. However, the number of useful biomarkers in NP-SLE in clinical practice is disconcertingly modest. In some cases it is not clear whether the biomarker is truly involved in pathogenesis, or the result of non-specific pathophysiological changes in the nervous system (e.g., neuroinflammation) or whether it is the consequence of a concomitant underlying abnormality related to SLE activity. In order to improve the diagnosis of NP-SLE and provide a better targeted care to these patients, there is still a need to develop and validate a range of biomarkers that reliably capture the different aspects of disease heterogeneity. This article critically reviews the current state of knowledge on laboratory and neuroimaging biomarkers in NP-SLE, discusses the factors that need to be addressed to make these biomarkers suitable for clinical application, and suggests potential future research paths to address important unmet needs in the NP-SLE field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2018.00340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288259PMC
December 2018

Clinical and radiological outcomes of 5-year drug-free remission-steered treatment in patients with early arthritis: IMPROVED study.

Ann Rheum Dis 2018 Jan 28;77(1):111-118. Epub 2017 Sep 28.

Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Objectives: To determine the 5-year outcomes of early remission induction therapy followed by targeted treatment aimed at drug-free remission (DFR) in patients with early arthritis.

Methods: In 12 hospitals, 610 patients with early (<2 years) rheumatoid arthritis (RA) or undifferentiated arthritis (UA) started on methotrexate (MTX) 25 mg/week and prednisone (60 mg/day tapered to 7.5 mg/day). Patients in early remission (Disease Activity Score <1.6 after 4 months) were randomised (single blind) to arm 1, adding hydroxychloroquine 400 mg/day and sulfasalazine 2000 mg/day, or arm 2, switching to MTX plus adalimumab 40 mg/2 weeks. Treatment adjustments over time aimed at DFR. Outcomes were remission percentages, functional ability, toxicity and radiological damage progression after 5 years.

Results: After 4 months, 387 patients were in early remission, 83 were randomised to arm 1 and 78 to arm 2. After 5 years, 295/610 (48%) patients were in remission, 26% in sustained DFR (SDFR) (≥1 year) (220/387 (57%) remission and 135/387 (35%) SDFR in the early remission group, 50% remission, 11% SDFR in the randomisation arms without differences between the arms). More patients with UA (37% vs 23% RA, p=0.001) and more anticitrullinated protein antibody (ACPA)-negative patients (37% vs 18% ACPA-positive, p<0.001) achieved SDFR.Overall, mean Health Assessment Questionnaire was 0.6 (0.5), and median (IQR) damage progression was 0.5 (0-2.7) Sharp/van der Heijde points, with only five patients showing progression >25 points in 5 years.

Conclusions: Five years of DFR-steered treatment in patients with early RA resulted in almost normal functional ability without clinically relevant joint damage across treatment groups. Patients who achieved early remission had the best clinical outcomes. There were no differences between the randomisation arms. SDFR is a realistic treatment goal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2017-211375DOI Listing
January 2018

Protein array autoantibody profiles to determine diagnostic markers for neuropsychiatric systemic lupus erythematosus.

Rheumatology (Oxford) 2017 08;56(8):1407-1416

Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital Academic Medical Center.

Objective: The aim was to investigate the association between autoantibodies (autoAbs) and neuropsychiatric (NP) involvement in patients with SLE and to evaluate whether any autoAb or a combination of these autoAbs could indicate the underlying pathogenic process.

Methods: Using a multiplexed protein array for 94 antigens, we compared the serum autoAb profiles of 69 NPSLE patients, 203 SLE patients without NP involvement (non-NPSLE) and 51 healthy controls. Furthermore, we compared the profiles of NPSLE patients with clinical inflammatory (n = 38) and ischaemic (n = 31) NP involvement.

Results: In total, 75 IgG and 47 IgM autoAbs were associated with SLE patients in comparison with healthy controls. Comparing NPSLE with non-NPSLE and healthy control sera, 9 IgG (amyloid, cardiolipin, glycoprotein 2, glycoprotein 210, heparin, heparan sulphate, histone H2A, prothrombin protein and vimentin) and 12 IgM (amyloid, cardiolipin, centromere protein A, collagen II, histones H2A and H2B, heparan sulphate, heparin, mitochondrial 2, nuclear Mi-2, nucleoporin 62 and vimentin) autoAbs were present at significantly different levels in NPSLE. The combination of IgG autoAbs against heparan sulphate, histone H2B and vimentin could differentiate NPSLE from non-NPSLE (area under the curve 0.845, 99.97% CI: 0.756, 0.933; P < 0.0001). Compared with non-NPSLE, four IgG and seven IgM autoAbs were significantly associated with inflammatory NPSLE. In ischaemic NPSLE, three IgG and three IgM autoAbs were significantly different from non-NPSLE patients.

Conclusion: In our cohort, the presence of high levels of anti-heparan sulphate and anti-histone H2B combined with low levels of anti-vimentin IgG autoAbs is highly suggestive of NPSLE. These results need to be validated in external cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kex073DOI Listing
August 2017

Value of multidisciplinary reassessment in attribution of neuropsychiatric events to systemic lupus erythematosus: prospective data from the Leiden NPSLE cohort.

Rheumatology (Oxford) 2017 10;56(10):1676-1683

Department of Rheumatology, Leiden University Medical Center, Leiden.

Objective: To determine the contribution of reassessment in the attribution process of neuropsychiatric (NP) events to SLE or other aetiologies in a large, prospective and multidisciplinary assessed NPSLE cohort and to compare these results with other available attribution models for NP events occurring in SLE.

Methods: Three hundred and four consecutive SLE patients presenting NP events were evaluated. All subjects underwent standardized multidisciplinary medical, neuropsychological, laboratory and radiological examination on the inclusion and reassessment dates. Diagnosis was always established by multidisciplinary consensus. The final diagnosis after reassessment also took into account disease course and response to treatment. These data were compared with currently available attribution models for NP events in SLE.

Results: A total of 463 NP events were established. After reassessment, attribution to SLE was discordant in 64 (13.8%) NP events when compared with the first visit. We show that 14.5% of NP events previously attributed to SLE reclassified as non-NPSLE. In 86.4% of these patients immunosuppressive therapy was started after the first visit. When reassessment and available attribution models were compared, NPSLE cases overlapped considerably. Although specificity was high for all comparisons (0.81-0.95), an important variation in sensitivity (0.39-0.83) and agreement estimates (κ = 0.29-0.68) was observed. The Italian algorithm showed the highest sensitivity and specificity (>0.80) and moderate agreement (0.59-0.64).

Conclusion: In clinical practice NP events presenting in SLE are too often attributed to an immune-mediated origin. Multidisciplinary reassessment avoids misclassification in NPSLE. Multidisciplinary reassessment is the reference standard in NP events presenting in SLE and cannot be replaced by available attribution models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kex019DOI Listing
October 2017

C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus.

Front Immunol 2016 27;7:647. Epub 2016 Dec 27.

Department of Rheumatology, Leiden University Medical Center , Leiden , Netherlands.

C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (CP) (C1r/C1s, C2, or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC-producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q, but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore, we provide a literature overview of NP-SLE in C1q deficiency and hypothesize about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q-deficient individuals is more severe when compared with complement competent NP-SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective CP, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and, subsequently, some of its biological functions may be associated with more severe NP-SLE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2016.00647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5186770PMC
December 2016

Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement.

Rheumatology (Oxford) 2017 01 25;56(1):77-86. Epub 2016 Oct 25.

Department of Pathology.

Objectives: Neuropsychiatric (NP) involvement is a poorly understood manifestation of SLE. We studied post-mortem histopathology in relation to clinical NPSLE syndromes and complement deposition in brains of NPSLE and SLE patients and controls. Furthermore, we investigated the correlation between cerebral post-mortem histopathology and ex vivo 7 T MRI findings in SLE and NPSLE.

Methods: A nationwide search for autopsy material yielded brain tissue from 16 NPSLE and 18 SLE patients. Brains obtained from 24 patients who died of acute cardiac events served as controls. Apart from a histopathological evaluation, paraffin-embedded cortical tissue was stained for components of the classical, lectin and terminal complement pathways.

Results: Diffuse vasculopathy, microinfarction, macroinfarction, vasculitis and microthrombi occurred significantly more often in NPSLE than SLE patients and were absent in controls. Focal vasculopathy was found in both SLE patients and controls. Complement deposition was strongly associated with both SLE and NPSLE, but not with controls (P < 0.001). Microthrombi were found uniquely in NPSLE and were associated with C4d and C5b-9 deposits (P < 0.05). A 7 T MRI was unable to detect most small vessel injury that was visible histopathologically.

Conclusion: Our study demonstrates that histopathological lesions in NPSLE represent a continuum, ranging from non-specific lesions such as focal vasculopathy, to more specific lesions including C4d- and C5b-9-associated microthrombi and diffuse vasculopathy related to clinical syndromes defining NPSLE. Complement deposition may be a key factor in the interaction between circulating autoantibodies and thromboischaemic lesions observed in NPSLE. Therefore, complement inhibition may have novel therapeutic potential in NPSLE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/kew341DOI Listing
January 2017

Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus: results from two well-defined European cohorts.

Arthritis Res Ther 2016 12 3;18(1):289. Epub 2016 Dec 3.

Rheumatology/AIR, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Background: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data.

Methods: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available.

Results: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients.

Conclusions: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-016-1192-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135817PMC
December 2016

Glial and axonal changes in systemic lupus erythematosus measured with diffusion of intracellular metabolites.

Brain 2016 05 11;139(Pt 5):1447-57. Epub 2016 Mar 11.

C. J. Gorter Center for High Field MRI, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

Systemic lupus erythematosus is an inflammatory autoimmune disease with multi-organ involvement. Central nervous system involvement in systemic lupus erythematosus is common and results in several neurological and psychiatric symptoms that are poorly linked to standard magnetic resonance imaging outcome. Magnetic resonance imaging methods sensitive to tissue microstructural changes, such as diffusion tensor imaging and magnetization transfer imaging, show some correlation with neuropsychiatric systemic lupus erythematosus (NPSLE) symptoms. Histological examination of NPSLE brains reveals presence of cerebral oedema, loss of neurons and myelinated axons, microglial proliferation and reactive astrocytosis, microinfacrts and diffuse ischaemic changes, all of which can affect both diffusion tensor imaging and magnetization transfer imaging in a non-specific manner. Here we investigated the underlying cell-type specific microstructural alterations in the brain of patients with systemic lupus erythematosus with and without a history of central nervous system involvement. We did so combining diffusion tensor imaging with diffusion-weighted magnetic resonance spectroscopy, a powerful tool capable of characterizing cell-specific cytomorphological changes based on diffusion of intracellular metabolites. We used a 7 T magnetic resonance imaging scanner to acquire T1-weighted images, diffusion tensor imaging datasets, and single volume diffusion-weighted magnetic resonance spectroscopy data from the anterior body of the corpus callosum of 13 patients with systemic lupus erythematosus with past NPSLE, 16 patients with systemic lupus erythematosus without past NPSLE, and 19 healthy control subjects. Group comparisons were made between patients with systemic lupus erythematosus with/without past NPSLE and healthy controls on diffusion tensor imaging metrics and on diffusion coefficients of three brain metabolites: the exclusively neuronal/axonal N-acetylaspartate, and the predominantly glial creatine + phosphocreatine and choline compounds. In patients with systemic lupus erythematosus with past NPSLE, significantly higher diffusion tensor imaging mean and radial diffusivities were accompanied by a significantly higher intracellular diffusion of total creatine (0.202 ± 0.032 μm(2)/ms, P = 0.018) and total choline (0.142 ± 0.031 μm(2)/ms, P = 0.044) compared to healthy controls (0.171 ± 0.024 μm(2)/ms, 0.124 ± 0.018 μm(2)/ms, respectively). Total N-acetylaspartate, total creatine and total choline diffusion values from all patients with systemic lupus erythematosus correlated positively with systemic lupus erythematosus disease activity index score (P = 0.033, P = 0.040, P = 0.008, respectively). Our results indicate that intracellular alterations, and in particular changes in glia, as evidenced by increase in the average diffusivities of total choline and total creatine, correlate with systemic lupus erythematosus activity. The higher diffusivity of total creatine and total choline in patients with NPSLE, as well as the positive correlation of these diffusivities with the systemic lupus erythematosus disease activity index are in line with cytomorphological changes in reactive glia, suggesting that the diffusivities of choline compounds and of total creatine are potentially unique markers for glial reactivity in response to inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/aww031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006250PMC
May 2016

Predictive factors of radiological progression after 2 years of remission-steered treatment in early arthritis patients: a post hoc analysis of the IMPROVED study.

RMD Open 2016 15;2(1):e000172. Epub 2016 Feb 15.

Department of Rheumatology , Leiden University Medical Center , Leiden , The Netherlands.

Objectives: To identify predictive factors of radiological progression in early arthritis patients treated by remission-steered treatment.

Methods: In the IMPROVED study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (disease activity score (DAS) <1.6 after 4 months) tapered prednisone to zero. Patients not in early remission were randomised to arm 1: MTX plus hydroxychloroquine, sulfasalazine and prednisone, or to arm 2: MTX plus adalimumab. Predictors of radiological progression (≥0.5 Sharp/van der Heijde score; SHS) after 2 years were assessed using logistic regression analysis.

Results: Median (IQR) SHS progression in 488 patients was 0 (0-0) point, without differences between RA or UA patients or between treatment arms. In only 50/488 patients, the SHS progression was ≥0.5: 33 (66%) were in the early DAS remission group, 9 (18%) in arm 1, 5 (10%) in arm 2, 3 (6%) in the outside of protocol group. Age (OR (95% CI): 1.03 (1.00 to 1.06)) and the combined presence of anticarbamylated protein antibodies (anti-CarP) and anticitrullinated protein antibodies (ACPA) (2.54 (1.16 to 5.58)) were independent predictors for SHS progression. Symptom duration <12 weeks showed a trend.

Conclusions: After 2 years of remission steered treatment in early arthritis patients, there was limited SHS progression in only a small group of patients. Numerically, patients who had achieved early DAS remission had more SHS progression than other patients. Positivity for both anti-CarP and ACPA and age were independently associated with SHS progression.

Trial Registration Numbers: ISRCTN Register number 11916566 and EudraCT number 2006 06186-16.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/rmdopen-2015-000172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762208PMC
February 2016

Changes in White Matter Microstructure Suggest an Inflammatory Origin of Neuropsychiatric Systemic Lupus Erythematosus.

Arthritis Rheumatol 2016 08;68(8):1945-54

Leiden University Medical Center, Leiden, The Netherlands.

Objective: To assess white matter (WM) and gray matter (GM) magnetization transfer ratio histogram peak heights (MTR-HPHs) in different subsets of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) who have unremarkable findings on 3T magnetic resonance imaging of the brain and to evaluate whether these values could be used to highlight different clinically suspected underlying pathogenic processes or identify the clinical NPSLE status or whether they could be associated with a specific NPSLE syndrome.

Methods: Sixty-four SLE patients with neuropsychiatric symptoms were included. The initial NPSLE diagnosis and suspected underlying pathogenic process were established by multidisciplinary evaluation. The final diagnosis was made after also considering the disease course 6-18 months later. Thirty-three patients with central nervous system (CNS) NPSLE and 31 SLE patients with neuropsychiatric symptoms unrelated to SLE (non-SLE-related NP) were included. Twenty SLE patients without neuropsychiatric symptoms and 36 healthy control subjects were included for comparison. Differences in the WM and GM mean MTR-HPHs and between the different NPSLE subgroups (CNS NPSLE diagnosis, NPSLE phenotype [inflammatory or ischemic], and clinical changes after treatment) and the relationship to NPSLE syndromes were evaluated.

Results: Patients with inflammatory NPSLE had significantly lower WM MTR-HPHs than did the healthy controls, the SLE patients, and the non-SLE-related NP patients. Cognitive disorder, mood disorder, and psychosis were related to lower WM MTR-HPH values and cerebrovascular symptoms to higher values. Furthermore, the mean MTR-HPHs in the WM increased when the clinical status of the NPSLE patients improved.

Conclusion: Measurement of MTR-HPH of the WM has the potential to identify inflammatory NPSLE with CNS involvement. This finding underscores the usefulness of this technique for the detection of cerebral changes in NPSLE patients and for the assessment of clinical changes after treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.39653DOI Listing
August 2016

Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives.

Drugs 2016 Mar;76(4):459-83

Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a generic definition referring to a series of neurological and psychiatric symptoms directly related to systemic lupus erythematosus (SLE). NPSLE includes heterogeneous and rare neuropsychiatric (NP) manifestations involving both the central and peripheral nervous system. Due to the lack of a gold standard, the attribution of NP symptoms to SLE represents a clinical challenge that obligates the strict exclusion of any other potential cause. In the acute setting, management of these patients does not differ from other non-SLE subjects presenting with the same NP manifestation. Afterwards, an individualized therapeutic strategy, depending on the presenting manifestation and severity of symptoms, must be started. Clinical trials in NPSLE are scarce and most of the data are extracted from case series and case reports. High-dose glucocorticoids and intravenous cyclophosphamide remain the cornerstone for patients with severe symptoms that are thought to reflect inflammation or an underlying autoimmune process. Rituximab, intravenous immunoglobulins, or plasmapheresis may be used if response is not achieved. When patients present with mild to moderate NP manifestations, or when maintenance therapy is warranted, azathioprine and mycophenolate may be considered. When symptoms are thought to reflect a thrombotic underlying process, anticoagulation and antiplatelet agents are the mainstay of therapy, especially if antiphospholipid antibodies or antiphospholipid syndrome are present. Recent trials on SLE using new biologicals, based on newly understood SLE mechanisms, have shown promising results. Based on what we currently know about its pathogenesis, it is tempting to speculate how these new therapies may affect the management of NPSLE patients. This article provides a comprehensive and critical review of the literature on the epidemiology, pathophysiology, diagnosis, and management of NPSLE. We describe the most common pharmacological treatments used in NPSLE, based on both a literature search and our expert opinion. The extent to which new drugs in the advanced development of SLE, or the blockade of new targets, may impact future treatment of NPSLE will also be discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40265-015-0534-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791452PMC
March 2016

Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study).

Arthritis Res Ther 2016 Jan 21;18:23. Epub 2016 Jan 21.

Department of Rheumatology, Leiden University Medical Center, P.O. BOX 9600, Leiden, 2300 RC, The Netherlands.

Background: Early suppression of disease activity in (rheumatoid) arthritis (RA) patients may result in drug-free remission and prevent damage. We assessed 2-year clinical and radiological outcomes of two disease activity score (DAS)-remission-steered treatment strategies in early arthritis patients.

Methods: Patients (n = 610) with early RA or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (44/53 joints DAS <1.6) after 4 months tapered and stopped medication. Patients who did not achieve early DAS-remission were randomized to either MTX plus hydroxychloroquine plus sulphasalazine plus low dose prednisone (arm 1) or to MTX + adalimumab (arm 2). At four-monthly intervals, medication was tapered and stopped if DAS was <1.6 but restarted, increased or switched if DAS was ≥1.6. Proportions of (drug-free) DAS-remission (DFR) after 2 years and Sharp-van der Heijde scores (SHS) were analyzed separately for the treatment strategies and patients with RA and UA.

Results: After 2 years, 301/610 (49 %) patients were in DAS-remission and 131/610 (21 %) in DFR. In the early remission group 241/387 patients (62 %) were in DAS-remission and 111/387 (29 %) DFR. In arm 1 22/83 (27 %) and in arm 2 24/78 (31 %) were in DAS-remission, and 6/83 (7 %) and 7/78 (9 %), respectively, were in DFR. RA and UA patients achieved DAS-remission in comparable percentages (RA: 234/479 (49 %), UA: 64/122 (52 %), p = 0.25). More UA patients achieved DFR (41/122 (34 %)) compared to RA patients (89/479 (19 %), p<0.001). Mean (SD) DAS over time was 1.74 (0.58) across all patients, and median (IQR) SHS progression was 0 (0-0).

Conclusions: After 2 years remission-steered treatment in early RA and UA patients, DAS-remission and DFR percentages were relatively low. Patients who achieved early remission more often achieved (drug-free) remission after 2 years than patients who needed additional treatment steps in the randomization arms, and more UA than RA patients achieved DFR. Overall, disease activity and radiologic damage progression in all patients were well suppressed.

Trial Registration: http://www.controlled-trials.com/ISRCTN11916566 Registered 07/11/2006 and EudraCT number 2006-06186-16 Registered 16/07/2007.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13075-015-0912-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721018PMC
January 2016

Cluster analysis of an array of autoantibodies in neuropsychiatric systemic lupus erythematosus.

J Rheumatol 2014 Aug;41(8):1720-1

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands;

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3899/jrheum.140027DOI Listing
August 2014

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study.

Arthritis Res Ther 2013 Oct 31;15(5):R173. Epub 2013 Oct 31.

Introduction: The aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.

Methods: In this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.

Results: During year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.

Conclusions: In early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.

Trial Registrations: ISRCTN11916566 and EudraCT2006-006186-16.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/ar4361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978457PMC
October 2013

Demyelinating disease in SLE: is it multiple sclerosis or lupus?

Best Pract Res Clin Rheumatol 2013 Jun;27(3):405-24

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:

Among the 12 systemic lupus erythematosus (SLE)-related central nervous system (CNS) syndromes defined by the American College of Rheumatology (ACR), demyelinating syndrome and myelopathy are two of the less prevalent and more poorly understood ones. One important issue concerning demyelinating disease in SLE is that it can be easily misdiagnosed with other central nervous system demyelinating disorders such as multiple sclerosis (MS). A clinically isolated neurological syndrome can be the presenting feature before other concomitant symptoms of SLE appear or definite MS is diagnosed. Although challenging, some diagnostic tests used in clinical practice and research may help to differentiate between these entities. These tests have improved the understanding of the pathogenesis in these diseases, but some points, such as the role of antiphospholipid antibodies in SLE-associated transverse myelitis, remain unclear and are a matter of ongoing debate. This review discusses clinical, pathophysiological, radiological and therapeutic concepts of demyelinating disease of the CNS in SLE, focussing on its differentiation from MS and its relation with other CNS demyelinating processes, such as transverse myelitis, optic neuritis and neuromyelitis optica.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.berh.2013.07.010DOI Listing
June 2013

Neuropsychiatric manifestations in patients with systemic lupus erythematosus: epidemiology and radiology pointing to an immune-mediated cause.

Ann Rheum Dis 2013 Apr 19;72 Suppl 2:ii76-9. Epub 2012 Dec 19.

Department of Rheumatology, C1-R, Leiden University Medical Center, PO Box 9600, Leiden 2300 RC, The Netherlands.

Background: Different pathogenetic pathways have been proposed for neuropsychiatric (NP) manifestations in systemic lupus erythematosus (SLE).

Objective: To describe the patient characteristics of a large cohort of patients with SLE with NP manifestations (NPSLE) in a single centre and to review whether these and other data are compatible with immune-mediated mechanisms.

Methods: A total of 212 patients were identified from MRI scans of the brain ordered for suspected NPSLE. Data were collected from the medical records. NP syndromes were classified according to the American College of Rheumatology (ACR) nomenclature and case definitions.

Results: 155 patients fulfilled the criteria for SLE. In 102 patients NP manifestations were attributed to SLE itself (primary NPSLE) whereas, in the remaining patients, the NP symptoms were due to other causes. The median age at the time of SLE diagnosis in patients with primary NPSLE was 27.5 years and the median duration prior to NPSLE was 2.8 years. Forty patients (39%) had a NP manifestation in the first year of the disease. Cerebrovascular disease, cognitive dysfunction, seizures and headache were the most prevalent syndromes. In 47% of patients with primary NPSLE the MRI scan of the brain showed no abnormalities.

Conclusions: Most NP manifestations in SLE occur early in the disease. This finding, as well as data from quantitative imaging studies and recent pathological studies, point to an immune-mediated pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2012-202369DOI Listing
April 2013

Prospective study of clinical phenotypes in neuropsychiatric systemic lupus erythematosus; multidisciplinary approach to diagnosis and therapy.

J Rheumatol 2012 Nov 15;39(11):2118-26. Epub 2012 Sep 15.

Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.

Objective: To describe clinical phenotypes in neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods: Data were prospectively collected in the Leiden NPSLE referral clinic, where patients suspected of having NPSLE are assessed in a standardized multidisciplinary manner. In consensus meetings, all medical specialists agreed on therapeutic strategy based on the suspected pathogenetic mechanism of NPSLE in the individual patient. An algorithm illustrates the process of decision-making during the consensus meeting. Clinical phenotypes are described, classified by pathogenetic mechanism.

Results: One hundred consecutive patients were evaluated, of whom 71 had SLE (29 patients did not fulfill ≥ 4 American College of Rheumatology criteria) and 46 had NPSLE. Primary NPSLE was diagnosed in 38 patients (53%) and could be differentiated in 21 patients (55%) with inflammatory NPSLE who were advised on immunosuppressive therapy, 12 patients (32%) with ischemic NPSLE who were advised on anticoagulant therapy, and 5 patients (13%) with undefined NPSLE who were advised symptomatic treatment only. Cognitive dysfunction and higher level of disease activity were associated with inflammatory NPSLE. Although presence of immunoglobulin G anticardiolipin antibodies and abnormalities on magnetic resonance imaging (MRI) were associated with ischemic NPSLE, abnormalities on MRI lacked specificity to distinguish phenotypes. A history of renal disease and use of corticosteroids were associated with secondary NPSLE.

Conclusion: We describe multidisciplinary consensus as a standard for diagnosing and defining phenotypes in NPSLE. These phenotypes show specific characteristics, which can be used to support diagnosis and guide therapeutic decisions. Clinical phenotyping and selection of patients becomes increasingly important when advances in experimental science lead to new targets for therapy in NPSLE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3899/jrheum.120545DOI Listing
November 2012

Needs and preferences regarding health care delivery as perceived by patients with systemic sclerosis.

Clin Rheumatol 2011 Jun 18;30(6):815-24. Epub 2011 Jan 18.

Department of Rheumatology, C-01-Q, Leiden University Medical Center, 2300, RC, Leiden, The Netherlands.

This study aims to examine the needs and preferences regarding the delivery of health care services and information provision and their determinants in patients with systemic sclerosis (SSc). A questionnaire was sent to 77 SSc outpatients, comprising 27 items on health care needs within the domains physical, psychological, social support, employment/daily activities, or other health problems and 13 items on information needs. Moreover, the patients' preferences regarding the provision of health care services and information were listed. Additional assessments included sociodemographic characteristics, physical functioning (SSc Health Assessment Questionnaire), and quality of life (SF-36). Sixty-four patients (83%) returned the questionnaire. Twenty-six patients (41%) reported one or more unmet health care needs, with the highest proportions of patients with unmet needs seen in the physical (28%) and psychological (20%) domain. The highest percentages of patients with information needs were observed for medical subjects (20-28%). A lower mental component summary scale score and younger age were associated with the presence of at least one health care need in the psychological domain. Worse physical functioning, a diagnosis of diffuse SSc and having a partner were associated with higher information need score. A yearly, standardized multidisciplinary assessment program was most frequently mentioned as a preferred, but not yet existing health care model (59%) and the rheumatologist as a preferred source of information supply (75%). Unmet health care and information needs are common among SSc patients. To improve SSc health care, more attention should be paid to health care services for specific physical and psychological problems and medical information supply by the rheumatologist. In addition, the development of new models of care, such as a yearly, standardized multidisciplinary diagnostic program seems warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10067-010-1645-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101347PMC
June 2011

Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts.

Arthritis Rheum 2010 Dec;62(12):3716-21

Leiden University Medical Center, Leiden, The Netherlands.

Objective: The aim of this study was to determine whether there are differences in white matter integrity between systemic lupus erythematosus (SLE) patients and healthy controls, as determined using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging data.

Methods: Twelve patients with SLE (mean age 42 years [range 15-61 years]) diagnosed according to the American College of Rheumatology 1982 revised criteria for SLE and 28 healthy controls (mean age 46 years [range 21-61 years]) were included in the study. Magnetic resonance imaging was performed on a 3.0T scanner. Fractional anisotropy (FA) maps were calculated for each patient. TBSS analysis was used to compare the FA maps. The TBSS technique projects the FA data into a common space through the use of an initial approximate nonlinear registration, followed by projection onto an alignment-invariant tract representation (mean FA skeleton). The cluster results were corrected for multiple comparisons across space, and a threshold of significance of 0.05 was used.

Results: The white matter of tracts in the inferior fronto-occipital fasciculus, the fasciculus uncinatus, as well as the fornix, the posterior limb of the internal capsule (corticospinal tract), and the anterior limb of the internal capsule (anterior thalamic radiation) of patients with SLE showed reduced integrity as compared with normal subjects.

Conclusion: In this preliminary study, the integrity of white matter tracts in areas around limbic structures and in the internal capsule was found to be reduced. Larger studies could improve our understanding of the pathologic mechanisms behind the reduced white matter tract integrity in SLE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/art.27717DOI Listing
December 2010

Perfusion MRI in neuro-psychiatric systemic lupus erthemathosus.

J Magn Reson Imaging 2010 Aug;32(2):283-8

Radiology, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands.

Purpose: To use perfusion weighted MR to quantify any perfusion abnormalities and to determine their contribution to neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE).

Materials And Methods: We applied dynamic susceptibility contrast (DSC) perfusion MRI in 15 active NPSLE, 26 inactive NPSLE patients, and 11 control subjects. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were reconstructed and regions of interest were compared between groups. In addition, the effect of SLE criteria, NPSLE syndromes, immunological coagulation disorder, and medication on CBF, CBV, and MTT was investigated.

Results: No significant differences were found between the groups in CBF, CBV, and MTT. No significant influence of SLE criteria or NPSLE syndromes on CBF, CBV, or MTT was found. No significant influence of anti-cardiolipin antibodies, lupus anti-coagulant, the presence of anti-phospholipid syndrome (APS), or medication on CBF, CBV, or MTT was found.

Conclusion: Our findings suggest CBF, CBV, and MTT in the white and the gray matter in SLE patients is not significantly different from healthy controls or between patients with and without specific symptoms or with and without immunological disorder involving coagulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.22251DOI Listing
August 2010
-->